The present invention relates to a process for the preparation of a carbocyclic purine nucleoside analogue of formula (I), its salts and pharmaceutically acceptable derivatives thereof. An enantiomerically pure compound of formula (I) 
has been described in GB-A-2217320 and can be used as an intermediate in the:manufacture of abacavir, a 2-aminopurine nucleoside analogue with the following structure (II) 
This is described in EP 0434450 as having potent activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV).
There exists a need to synthesise large quantities of abacavir for clinical trials and once abacavir has been approved by the national medicine regulatory agencies, large quantities of abacavir will also be required for sale as a prescription medicine for the treatment of HIV infections.
Processes for the manufacture of abacavir using enantiomerically pure compounds of formula (III) 
via the 2-aminopurine intermediate of formula (I) are described generally-in PCT Publication Nos. WO91/15490, in WO95/21161, in EP 0434450 and in Tetrahedron: Asymmetry Vol. 4, p.1117, (1993). However, the procedures described provide an unsatisfactory route to the 2-aminopurine derivative of formula (I), inasmuch as they require the isolation and purification of a number of intermediates resulting in a relatively high cost and a low yield for the synthesis.
We have developed a process for the production of the intermediate of formula (I) from N-protected-4-amino-cyclopentenes of formula (IV) 
wherein P is a protecting group,
which provides a high yield and is more cost effective. The protecting group P will desirably be an acyl or substituted oxycarbonyl group.
One aspect of the present invention comprises an in situ conversion of cyclopentenes of formula (IV) to 2-aminopurine derivatives of formula (I) easily and conveniently without the need to isolate any intermediates. In our procedure, the deprotection of the starting material of formula (IV) in situ provides the desired amino alcohol without any wasteful workup, and because of the direct coupling and cyclisation, again without any work up or isolation of intermediates, the overall yield of the process is increased.
According to a further aspect of the invention, therefore, we provide a process for the preparation of a compound of formula (I), 
optionally in the form of its salt or complex, which comprises hydrolysing a compound of formula (IV) as defined above in the presence of acid, condensing the product of formula (V) formed 
in situ in the presence of a base with a compound of formula (VI) 
in which R represents CHO or H, followed by ring closure in situ of the resulting intermediate of formula (VII) 
in which R represents CHO or H, to produce a compound of formula (I), which can then be optionally reacted with an acid or complexing agent to form its salt or complex.
As described above, preferred protecting groups in the compound of formula (IV) are acyl or substituted oxycarbonyl groups. Preferred acyl groups include formyl or lower alkanoyl (having e.g. 1 to 4 carbon atoms in the alkyl portion), especially an acetyl group. Preferred substituted oxycarbonyl groups will be of the formula Rxe2x80x2 OC(O)xe2x80x94, wherein Rxe2x80x2 may be an alkyl or aralkyl group. A preferred! alkyl group is tert butyl; a preferred aralkyl group is benzyl.
The hydrolysis step is preferably achieved by mild acid-catalysed hydrolysis in an organic solvent, such as an alkanol, a cyclic ether or a chlorinated hydrocarbon. It is preferred to use an organic or mineral acid such as trifluoroacetic acid or hydrochloric acid in an alkanol solvent such as industrial methylated spirit (IMS), optionally in the presence of water.
The condensation step is then carried out without any isolation of the hydrolysis product of formula (V) This condensation reaction is preferably carried out under reflux in a polar solvent such as an alcohol, e.g. ethanol or butanol, or water or acetonitrile, or mixtures thereof, in the presence of at least sufficient base to neutralise both the acid used for the hydrolysis and that produced during the condensation. Generally, there will be at least 2 equivalents based on the amount of compound of formula (IV). The base will desirably be a trialkylamine or an alkali metal carbonate or bicarbonate, e.g. potassium or sodium carbonate, and more preferably, sodium bicarbonate. Preferred combinations are triethylamine or sodium bicarbonate in IMS. The group R in the compound of formula (VI) preferably represents CHO.
The ring closure reaction is then carried out, again without any isolation of any preceding intermediate product of formula (VII). This is conveniently carried out using trialkylorthoformates in the presence of concentrated aqueous or anhydrous mineral acid, optionally in the presence of one or more non-aqueous solvents, e.g. tetrahydrofuran, ethyl acetate or IMS. Suitably, the unisolated product of formula (VII) is added to a mixture of acid and a trialkylorthoformate. A preferred combination comprises use of from about 1.5 to 3, preferably around 2 molar equivalents of hydrochloric acid in triethylorthoformate, which results in precipitation of the hydrochloride salt of the 9-substituted-2-amino purine of formula (I). The free base may, if desired, be liberated by treatment with base.
The process of the invention has been found to provide yields of compounds of formula (I) starting from a compound of formula. (IV) of in excess of 80%. This compares very favourably with yields of compounds of formula (I) which are obtained using earlier stepwise procedures in which the intermediates are isolated, which give, typically around 56% when the compound of formula (III) is used as starting material, or yields of around 75% when the procedure described in Publication No. WO95/21161 is used, starting from a compound of formula (V).
The compounds of formula (VI) can be synthesised by a method as described in WO95/21161. The compound can be synthesised from the readily available 2,5-diamino-4,6-dihydroxypyrimidine, by reacting this with a Vilsmeier reagent of formula (VIII) 
to form a compound of formula (IX) 
(wherein in both formulae (VIII) and (IX), R1 and R2 are as defined in WO95/2:1161, viz: that R1 and R2, which may be the same or different are selected from C1-8 straight-chain alkyl, C1-8 branched alkyl, C3-8 cycloalkyl, and aryl groups (such as phenyl or naphthyl), which may be optionally substituted, for example by C1-4 alkyl or halogen (e.g. C1). In a preferred embodiment of the invention R1 and R2 are both methyl), followed by hydrolysis.
Compounds of formula (VIII) may be prepared from a variety of formamides of secondary amines by reaction with a variety of acid halides, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosgene, and oxalyl chloride, for example as detailed in a review by C. M. Marson, Tetrahedon 1992, 48:3660-3720 and references therein.
The compound of formula (VI) where R is H can be prepared from the compound of formula (IX) by hydrolysis in acidic solution, e.g. at pH 3xc2x10.5, by adding a water miscible cosolvent, such as ethanol. The compound of formula (VI) where R is CHO can also be prepared by the hydrolysis of the compound of formula (IX) in the minimum of water, with the pH controlled as described above. Under these conditions the compound of formula (VI) where R is CHO precipitates as formed and can be filtered off.
The compound of formula (IV) may be prepared by methods analogous to those described in Tetrahedron: Asymmetry Vol.4, p.1117 (1993).